Postoperative cognitive dysfunction (POCD), common in elderly patients, refers to a decline in cognitive function following surgery, which may persist or even evolve into Alzheimer's disease (AD). Despite great efforts, the mechanism of POCD remains unclear. In the present study, we tested the hypothesis that Toll-like receptor 4 (TLR4) on microglia contributes to POCD. Shortly after surgery, aged rats demonstrated significant deficits in memory and learning, accompanied by the activation of microglia, marked upregulation of TLR4 on microglia in the hippocampus, as well as an increased expression of two downstream factors [myeloid differentiation factor 88 (MyD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF)] and pro-inflammatory cytokines [including tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β)]. With an increase in time following surgery, the expression of TLR4 and the aforementioned factors and pro-inflammatory cytokines gradually returned to normal, as did the cognitive function of the aged rats. In conclusion, our study suggests that the activation of TLR4 signaling on microglia may act as an underlying mechanism of POCD.
Single-chain Fv fragments (scFvs) consist of the variable heavy-chain (VH) and variable light-chain (VL) domains, which are the smallest immunoglobulin fragments containing the whole antigen-binding site. Human soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) proves to acquire a potent pro-apoptotic activity only after selective binding to a predefined tumor cell surface antigen and has no off-target effects towards normal cells. Glioblastoma multiforme (GBM) is the most frequent and aggressive type of brain tumor and overexpresses human multidrug resistance protein 3 (MRP3). In this study, we designed a novel fusion protein, termed scFvM58-sTRAIL, in which the MRP3-specific scFv antibody M58 was genetically fused to the N-terminus of human soluble TRAIL (sTRAIL). The recombinant scFvM58-sTRAIL fusion protein, expressed in Escherichia coli, was purified by chromatography and tested for cytotoxicity. scFvM58-sTRAIL showed a significant apoptosis-inducing activity towards MRP3-positive GBM cells in vitro. The pro-apoptotic activity of scFvM58-sTRAIL towards GBM cells was strongly inhibited in the presence of the parental scFvM58 antibody, suggesting that cytotoxic activity is MRP3-restricted. In a control experiment with MRP3-negative Jurkat cells, scFvM58-sTRAIL did not induce apparent apoptosis. In addition, through target antigen-restricted binding, scFvM58-sTRAIL was capable of activating not only TRAIL-R1 but also TRAIL-R2. In conclusion, our results suggest that fusion protein scFvM58-sTRAIL with specificity for MRP3 is a highly selective therapeutic agent and may provide an alternative therapy for human GBM.
BackgroundAlthough many studies have shown glycogen synthase kinase-3β(GSK-3β) was associated with type 2 diabetes mellitus(T2DM) and implicated with a wide range of cancers, the role of GSK-3β in hepatocellular carcinoma(HCC) and the correlation among GSK-3β, T2DM and HCC remains unclear. Our objectives were to identify the effect of p-Ser9-GSK-3β on the prognosis of patients with HCC and to learn more about the interaction among T2DM, GSK-3β and the prognosis of HCC.MethodsFirstly we used reverse transcriptase-PCR(RT-PCR) and western blotting to determine the expression levels of GSK-3β and p-Ser9-GSK-3β in human HCC samples. We then used immunohistochemical staining to evaluate the expression pattern of p-Ser9-GSK-3β in 178 patients with HCC after curative partial hepatectomy. Finally we statistically analyzed the association of p-Ser9-GSK-3β and T2DM with the prognosis of patients with HCC.ResultsP-Ser9-GSK-3β was over-expressed in tumor tissues compared with their normal counterparts. Correlation and regression analysis indicated that the over-expression of p-Ser9-GSK-3β was significantly associated with T2DM, and the correlation coefficient was 0.259 (P = 0.001). Multivariate analysis showed that the over-expression of p-Ser9-GSK-3β(P<0.001) and T2DM(P = 0.008) were independently associated with poor prognosis of HCC, respectively. Further analysis demonstrated that these two variables are closely related with each other.ConclusionThe over-expression of p-Ser9-GSK-3β and T2DM are strongly correlated with worse surgical outcome of HCC. P-Ser9-GSK-3β may play a significant role in mediating the influence of T2DM on the prognosis of HCC.
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